Targeted reduction of KLF6-SV1 restores chemotherapy sensitivity in resistant lung adenocarcinoma

Sangodkar, Jaya; DiFeo, Analisa; Feld, Lauren D.; Bromberg, Romina; Schwartz, Richard S.; Huang, Fei; Terzo, Esteban A.; Choudhri, Aisha; Narla, Goutham

doi:10.1016/j.lungcan.2009.02.014

Cited by 21 publications

(28 citation statements)

References 20 publications

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“…After the cells were either treated with a drug or transfected with siRNA, they were stained with propidium iodide to ascertain the DNA content and determine cell cycle distribution within the cell population as previously described (44). Sub-G1 peaks were analyzed on DNA histograms; hypodiploid DNA represented dead cells.…”

Section: Methodsmentioning

confidence: 99%

“…A pSUPER vector encoding luciferase shRNA was used as a control. Stable cell lines of HCC827 were generated by retroviral transfection of the pSUPER-shLuciferase (shLuc) and pSUPER-shKLF6 (shKLF6) and selected with 2 μg/ml puromycin as described previously (44). Polyclonal pools of the shRNA-infected cell lines were collected, and KLF6 knockdown was determined by qRT-PCR and Western blotting.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor volume was assessed weekly as previously described (44), until volumes reached an average of 200 mm 3 . The following treatments were administered via intraperitoneal injection: vehicle control (DMSO), erlotinib (25 mg/kg), TFP (10 mg/kg), and combination erlotinib (25 mg/kg) and TFP (10 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

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Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response

Sangodkar¹,

Dhawan²,

Melville³

et al. 2012

J. Clin. Invest.

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EGFR activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms, including activation of AKT signaling. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR-based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. We identified a transcriptional network involving the tumor suppressors Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma. Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response

Sangodkar¹,

Dhawan²,

Melville³

et al. 2012

J. Clin. Invest.

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“…Furthermore, it has been shown that functional inactivation of KLF6 in various types of cancers such as prostate, ovary and colon, is caused by somatic mutations, loss of heterozygosity (LOH) and silencing by hypermethylation of its promoter Cho et al, 2006;Sangodkar et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone Role in the Expression of KLF6 Caco-2 Colon Cancer Cells

Rojas

Laime

2017

Int. J. Morphol.

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SUMMARY:Kruppel-like factor 6 (KLF6) is a member of the family of Kruppel transcription factors, this plays an important role in the regulation of cell growth, differentiation and angiogenesis. Rosiglitazone is a PPARy agonist drug, its antitumor effect has been described in models of breast and colon cancer. The aim of this study is to evaluate the level of expression of KLF6 in Caco2 cells treated with Avandia. For this a Immunofluorescence was performed, the Caco2 cells were cultured and treated with Rosiglitazone, another group was treated with Rosiglitazone and GW-9662, inhibitor for Immunofluorescence an anti-KLF6 antibody and a secondary antibody coupled to Alexa-488 was used . Cells were observed in a fluorescence microscope and images were processed. The results show that KLF6 is expressed in the cytoplasm of cells Caco2. Compared to treatment with Avandia, KLF6 increases its expression in the cytoplasm. When cells were treated with GW-9662 inhibitor, an expression of KLF6 in the nucleus was observed. KLF6 expression in the cytoplasm of cells Caco2, could be explained by the knowledge of splicing variants SV1 and SV2, these abnormally accumulate in the cytoplasm and promotes cell growth. It is concluded that in untreated Caco 2 cells, KLF6 is expressed in the cytoplasm. Compared to treatment with Rosiglitazone, KLF6 upregulated in the cytoplasm and compared to treatment with the inhibitor, KLF6 is expressed in the nucleus of Caco 2 cells.KEY WORDS: KLF6; Rosiglitazone; Colon and KLF6.

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“…Increased expression of KLF6-SV1 contributes to chemo-resistance in lung cancer. Targeted reduction of KLF6-SV1 by RNA interference results in the induction of spontaneous apoptosis in cell culture synergizes with chemotherapeutic agents like cisplatin, and lead to significant tumor regression in vivo [21] . These observations emphasized the importance of investigation of alternative splicing genes in lung cancer for improving targeted therapy.…”

Section: Alternatively Spliced Genes As Therapeutic Targets In Lung Cmentioning

confidence: 99%

Roles of alternative splicing in the pathogenesis of lung cancer

2017

Can Cell Microenviron

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Alternative splicing contributes to the vast complexity of mRNA transcripts and protein isoforms. It has been estimated that the majority of protein-coding genes are subject to alternative splicing in humans. Alternative splicing plays a critical role in physiological processes and cell development programs, and dysregulation of alternative splicing is often associated with pathologic conditions such as cancer. Indeed, the abnormal splicing is frequently found in lung cancer, which produces various protein isoforms with properties that may have different functions and therefore even diverse effects on tumor malignant development. In this highlight, we summarize the evidence supporting the functional role of alternative splicing in lung cancer, discuss the regulation of alternative splicing, and highlight the relevance of splicing variation on lung cancer therapy.

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Targeted reduction of KLF6-SV1 restores chemotherapy sensitivity in resistant lung adenocarcinoma

Cited by 21 publications

References 20 publications

Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response

Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response

Rosiglitazone Role in the Expression of KLF6 Caco-2 Colon Cancer Cells

Roles of alternative splicing in the pathogenesis of lung cancer

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